ABSTRACT According to the NIH, Dental Caries is the most common chronic disease in children and adults in the US. Although it is highly preventable, it remains a significant public health problem and a misunderstood condition. Developmental defects of tooth mineralization, have been reported to increase risk of caries. While the role of extracellular matrix proteins and regulators of mineral ions homeostasis in tooth mineralization has been well studied, there is a gap in understanding the transcriptional regulation of this unique process and its impact on caries susceptibility. Genome-Wide Association Studies (GWAS) and studies of rare genetic diseases provide evidence that transcriptional regulation of formation of tooth mineralized tissues may be a contributing factor to the susceptibility to dental caries initiation and progression. The goal of the proposed research is to understand the molecular pathology underlying increased susceptibility to dental caries in patients with heterozygous mutations in the TRPS1 gene coding for the TRPS1 transcription factor. Using genetically modified mice and in vitro approaches, we will determine whether decreased mineralization of Trps1-deficient dental tissues affects the susceptibility to dental caries. Furthermore, we will delineate the interactions between Trps1 and Osx, two transcription factors regulating tooth development and mineralization, to determine molecular mechanisms, by which Trps1 regulates tooth mineralization. The specific aims of this study are (1) To establish the relationship between mineralization of dental tissues and increased susceptibility to dental caries in Trps1-deficiency, (2) To determine the role of Osx in Trps1-dependent initiation of mineralization, and (3) To delineate Trps1-Osx molecular interactions in odontoblasts. The experimental design employs Trps1+/- and Trps1 conditional knockout mice, analyses of molecular interactions and mineralization in cellular models, and advanced methodology of mineralized tissue assessment. The proposed research will provide better understanding of the impact of genetic factors and molecular pathways regulating the process of tooth mineralization, and how they affect susceptibility to dental caries. In addition, it may set foundation for the development of effective caries prevention strategies for individuals with genetically determined increased susceptibility to caries due to impaired tooth mineralization. The proposed research and training plan will provide the applicant with the comprehensive training in molecular biology of biomineralization and translational regulation of this process with an emphasis on dental mineralization defects as a caries risk factor. A team of experts in mineralized tissues and in dental caries research will provide the required training to facilitate the applicant?s career progress towards independence, focusing on translational research in cariology. The applicant?s career development plan includes courses/workshops, comprehensive experimental training in dental mineralized tissues combined with dental caries susceptibility analysis, performed under the guidelines of the mentoring team.